Aldehyde acetal based processes for the manufacture of macrocyclic depsipeptides and new intermediates

a technology of macrocyclic depsipeptides and aldehyde acetal, which is applied in the direction of peptides, immunoglobulins, peptide/protein ingredients, etc., can solve the problems of high cost, difficult preparation of ethers or analogues thereof, and low yield of fermentation with regard to any single of these compounds

Active Publication Date: 2014-04-10
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention describes a way to make a type of molecule called macrocyclic depsipeptides, and new methods to make the molecule's intermediates. This can be useful for making certain drugs and other molecules.

Problems solved by technology

Therefore, the yield of fermentation with regard to any single of these compounds is rather low.
Therefore its direct use and synthesis are not recommended.
In addition, the elimination of the oxidation step allows using N-Me-Tyosine or analogues instead of the protected variants such as t-butyl-ethers or analogues thereof which are expensive and difficult to prepare.

Method used

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  • Aldehyde acetal based processes for the manufacture of macrocyclic depsipeptides and new intermediates
  • Aldehyde acetal based processes for the manufacture of macrocyclic depsipeptides and new intermediates
  • Aldehyde acetal based processes for the manufacture of macrocyclic depsipeptides and new intermediates

Examples

Experimental program
Comparison scheme
Effect test

example 2

Synthesis of Compound a Using an Acyclic Acetal Protecting Group: Employing of the Dibenzyl Acetale

[0216]The following reaction scheme shows the use of compound 9 as an alternative to Compound 7 in Example 1:

[0217]In detail, the corresponding precursors and the reactions in the scheme are realized as follows:

2 A) Synthesis of the dibenzyl-acetale synthon (Compound 17)

[0218]Compound 17 was prepared according to the synthesis scheme shown below:

2 B) Synthesis of Compound 12

[0219]In a 3 L-reactor under nitrogen at 0° C., dried acrolein (105.3 g, 1.78 mol) in methylene chloride (1.15 kg) was introduced Trimethylbromosilane (281.7 g, 1.78 mol) was added dropwise over 30 min with a dropping funnel, keeping the temperature below 5° C. After 1 h 30 min of stirring, benzyl alcohol (311.1 g, 2.85 mol) was added dropwise over 45 min, and the mixture was stirred at 0° C. for 16 h. To the orange solution, pyridine (29 g, 0.36 mol), acetic anhydride (38 g, 0.36 mol) and DMAP (4.4 g, 0.04 mol) wer...

example 3

Shift of Equilibrium

[0239]A possible side reaction of the acetal cleavage and formation of ahp may result in the dehydrate form of Compound A. This can be converted easily (back) into Compound A using a simple procedure for hydration of the dehydrate form depicted in the following reaction scheme:

[0240]This allows to improve the yield of Compound A in any type of synthesis (be it chemical as in the present disclosure or by use of fermentation as in WO2009 / 024527).

[0241]For example, during cleavage of acid sensitive protecting groups in a compound comprising the ahp-subunit, e.g. Compound A in the Scheme before Example 1, the formation of large amounts of the corresponding dehydrated byproduct (Compound A-Dehydrate) is observed. This byproduct is usually separated e.g. by chromatography and disposed. This leads to loss of valuable product and to low yield for this step. For example, if the deprotection product(s) of Compound 8 are subjected to acidic conditions to cleave the trityl- ...

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Abstract

The invention relates to a method or process for the chemical manufacture of depsipeptides of the formula I employing an aldehyde acetal intermediate,wherein the symbols have the meaning defined in the description, to new intermediates and their manufacture, as well as related invention embodiments.

Description

SUMMARY OF THE INVENTION[0001]The invention relates to a method or process for the manufacture of macrocyclic depsipeptides, to new intermediates and their manufacture, as well as related invention embodiments.BACKGROUND OF THE INVENTION[0002]Cyclic depsipeptides have numerous uses in pharmacology. As an example, the depsipeptides disclosed in WO2009 / 024527 are useful for treatment of various diseases. For example, the compound of formula II mentioned in WO2009 / 024527 is useful for the treatment and prevention of inflammatory and / or hyperpoliferative and pruritic skin diseases such as atopic dermatitis, psoriasis, pustular psoriasis, rosacea, keloids, hypertrophic scars, acne, Netherton's syndrome or other pruritic dermatoses such as prurigo nodularis, unspecified itch of the elderly as well as other diseases with epithelial barrier dysfunction such as aged skin.[0003]Nostopeptin BN920, formerly isolated from the cyanobacterium Nostoc, was isolated also from Microcystis. Nostopeptin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K11/02C07C229/22C07K7/06C07D317/30
CPCC07K11/02C07K7/06C07C229/22C07D317/30C07K7/02C07K7/04C07C43/164C07C229/12C07C233/47C07K11/00
Inventor ACEMOGLU, MURATHELLSTERN, HERIBERTRISS, BERNARDSPRECHER, CHRISTIAN
Owner NOVARTIS AG
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